Predictive Approach Identifies Molecular Targets and Interventions to Restore Angiogenesis in Wounds With Delayed Healing

Abstract

Impaired angiogenesis is a hallmark of wounds with delayed healing, and currently used therapies to restore angiogenesis have limited efficacy. Here, we employ a computational simulation-based approach to identify influential molecular and cellular processes, as well as protein targets, whose modulation may stimulate angiogenesis in wounds. We developed a mathematical model that captures the time courses for platelets, 9 cell types, 29 proteins, and oxygen, which are involved in inflammation, proliferation, and angiogenesis during wound healing. We validated our model using previously published experimental data. By performing global sensitivity analysis on thousands of simulated wound-healing scenarios, we identified six processes (among the 133 modeled in total) whose modulation may improve angiogenesis in wounds. By simulating knockouts of 25 modeled proteins and by simulating different wound-oxygenation levels, we identified four proteins [namely, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and angiopoietin-2 (ANG-2)], as well as oxygen, as therapeutic targets for stimulating angiogenesis in wounds. Our modeling results indicated that simultaneous inhibition of TGF-β and supplementation of either FGF-2 or ANG-2 could be more effective in stimulating wound angiogenesis than the modulation of either protein alone. Our findings suggest experimentally testable intervention strategies to restore angiogenesis in wounds with delayed healing.

Cellular Mechanisms of FGF-Stimulated Tissue Repair

“…It is noteworthy that Nagaraja et al [ 144 ], using mathematical modeling based on a compendium of experimental data, identified FGF2 as one of five critical factors required for restorative angiogenesis in wounds with delayed healing. The other four factors include TGFβ, angiopoietin 2, VEGF, and oxygen.…”

Stromal vascular fraction promotes migration of fibroblasts and angiogenesis through regulation of extracellular matrix in the skin wound healing process

“…New blood vessels help transport nutrients and oxygen to the wound area. In the wound healing process, growth of microvessels of the size of capillaries is required [38]. The proliferation and subsequent apoptosis of endotheliocyte, the proliferation and migration of fibroblasts, and the synthesis of collagen are all required to simultaneously occur in a coordinated fashion to promote wound closure.…”

“…Vascular and non-vascular cells coordinated to promote physiological healing of wounds. Interaction between capillary endothelial cells and peripheral cells are required to determine the remodeling process of microvessels [38]. Evidence suggests that microvascular dysfunction is responsible for the pathogenesis of diabetic wound healing [3].…”

Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)

“…Previous computational models have been developed to study mechanisms of cutaneous wound healing 2,14,22,32,34,37 and to identify drug targets for stimulating angiogenesis in wound healing. 23 Almquist et al recently reported an empirical pharmacokinetic and pharmacodynamic model of AZD8601 in diabetic wound healing, which captures statistical variation in wound healing dynamics at both the individual and the population level using a nonlinear mixed effect (NLME) modelling approach. 1 While this model describes the time-dependent aspects of wound healing, it does not account for spatial heterogeneity of drug delivery and wound healing.…”